Biphenyl pyrazoles derivatives with affinity for cannabinoid receptors are described in U.S. Pat. No. 5,624,941 to Sanofi. In that patent, Compound 1, chemically described variously as N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; and as N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide;
Compound 1 and its pharmaceutically acceptable salts thereof are disclosed as useful antagonists of the cannabinoid CB1 receptor. Compound 1 is a generally highly selective agent, with little activity for the CB2 receptor and a wide variety of other central G-protein coupled receptors. It has also been reported to act as an antagonist of the neurokinin-3 receptor.
It is useful for the treatment or prevention of disorders including obesity, poorly regulated consumption desires, disorders associated with a substance, obesity associated with non-insulin-dependent diabetes, other diseases resulting in patients becoming overweight, bulimia, drug dependency, the desire to consume non-essential food items and the spontaneous appetency for a food item which usually brings pleasure, and neuroinflammatory pathology, particularly such pathology involving demyelinization, viral encephalitis, cerebrovascular accidents, or cranial trauma. See Maruani J and Soubrie P, U.S. Pat. No. 6,344,474 to Sanofi-Synthelabo; and Bourrie B and Casellas P, U.S. Pat. No. 6,642,258 to Sanofi-Synthelabo.
Also disclosed is the use of Compound 1 for the treatment or prevention of diarrhea; obesity in juvenile patients, including in cases of drug-induced obesity; dislipidemia and dislipidemia-associated diseases such as metabolic syndrome; Parkinson's disease; itch; sexual dysfunction; bone disorders; and hepatic diseases including liver fibrosis, alcoholic cirrhosis, chronic viral hepatitis non-alcoholic steatohepatitis, and primary liver cancer. See: Croci T and Manara L, PCT Patent Application WO03018060, Sanofi-Synthelabo Applicant; Benavides J et al., PCT Patent Application WO0185092, Aventis Applicant; Antel J et al., US Patent Application 20050101585, Solvay Applicant; Yasui K et al. PCT Patent Application WO03070277, Shionogi Applicant; Arone M, PCT Patent Application WO03082256, Sanofi-Synthelabo Applicant; Hamilton R S et al., PCT Patent Application WO2004078261, University of Aberdeen Applicant, Arone M, PCT Patent Application, WO2005046689, Sanofi-Aventis Applicant; Lotersztajn S et al., PCT Patent Application WO2005084652, Institut National de la Sante et de la Recherché Medicale and Sanofi-Aventis Applicants.
Compound 1A, chemically described as 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide, is a derivative of Compound 1 with a favorable pharmacological and bioavailability profile that is currently undergoing clinical evaluation; Thomas B F et al., J. Pharmacol. Exp. Ther. 1998 285: 285; Perio A et al., 14th Symp. Int. Cannabinoid Res. Soc. (Jun 22-Jun 27, Paestum) 2004, Abst 93; Rinaldi-Carmona M et al., J. Phannacol. Exp. Ther. 2004 310: 905.
Compound 1A and its pharmacologically acceptable salts and solvates have been disclosed as particularly powerful and selective CB1 antagonists with utility similar to that of Compound 1 as well as good activity in a model system of attention deficit disorder; Arnone M et al., PCT Patent Application WO2005046689, Sanofi-Synthelabo Applicant; Barth F et al., US Patent Application 20040039024, Sanofi-Synthelabo Applicant; Breul T et al., PCT Patent Application WO2005046690, Sanofi-Synthelabo Applicant; Louis, C.; et al. Behav. Pharmacol. 2005 16(Suppl. 1): Abst. A60. Compound 1A is also characterized by a longer duration of action than that of Compound 1 in animal models.
The combination of Compound 1 or 1A with additional agents extends or enhances its utility in the treatment of diabetes and obesity: Cheng P T W et al., U.S. Pat. No. 6,875,782 to Bristol-Myers Squibb, and US Patent Applications 20040063700, 20040063762, and 20050119312 Bristol-Myers Squibb, Applicant.
Additionally disclosed uses for Compound 1 or 1A include methods for its combination with additional appetite suppressants and lipase inhibitors to enhance its anti-obesity effects and to treat or prevent coronary artery disease: Nargund R P et al. US Patent Application 20040122033, Merck & Co. Applicant; Briggs M et al., US Patent Application 20040204472, Pharmacia Applicant; Weber E and Cowley M A et al., US Patent Application 20040254208; Gulve E A and McMahon E G, US Patent Application 20040214804, Pharmacia Applicant; Antel J et al., PCT Patent Application WO2005039579, Solvay Pharma Applicant.
Compounds 1 and 1A have been characterized by in vitro receptor binding studies to be highly selective for the CB1 vs. CB2 receptor and to have little affinity for a wide range of other neurological receptors. Rinaldi-Carmona M et al. FEBS Lett. 1994 350: 240; Thomas B F et al., J. Pharmacol. Exp. Ther. 1998 285: 285; Rinaldi-Carmona M et al., J. Pharmacol. Exp. Ther. 2004 310: 905.
Compounds 1 and 1A also reverse in vivo effects of cannabinoid agonists in rats, including hypothermia, ring immobility, and increased tail flick latency. Rats treated with Compound 1 demonstrate reduced sucrose and ethanol intake and, in obese rats, reduced food intake and body mass, along with greater insulin sensitivity. See e.g. Arnone M et al., Psychopharmacology 1997 132: 104; Trillou C R et al., Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003 284: R345; Perio A et al., 14th Symp. Int. Cannabinoid Res. Soc. (Jun 22-Jun 27, Paestum) 2004, Abst 93.
Compound 1 demonstrates excellent efficacy in reducing weight in obese patients and maintaining weight loss over a period of at least two years. Patients treated with Compound 1 also experienced significant increases in HDL cholesterol and reductions in blood triglycerides, as well as increased insulin sensitivity: Pi-Sunyer FX, Late-Breaking Clinical Trials III, American Heart Association Scientific Sessions 2004, Nov. 7-10, 2004, New Orleans, La.; Heshmati H M et al., Obes. Res. 2001 9(suppl 1):S70; and Van Gaal L F et al., Lancet 2005 365: 1389. Compound 1 is also effective in assisting patients to discontinue tobacco smoking: Dale L et al., Late-Breaking Clinical Trials II. American College of Cardiology Scientific Session 2004, Mar. 7-10, 2004, New Orleans, La.
In reports of these clinical trials Compound 1 was described as having a good safety profile with relatively low increases in serious adverse events across the different dose groups tested. However, it is clearly less well tolerated in higher doses, with the more common side effects including depression, anxiety, and irritability, and in some but not all studies, significant amounts of nausea. Even in a highly motivated Phase III clinical trial population, a considerable number of dose-dependent discontinuations occurred. First year adverse-event associated discontinuations in the RIO-North American trial were 7.2% for placebo versus 9.4% for the weakly efficacious 5 mg dose of Compound 1 and 12.8%, an increase of 77% versus placebo, for the more optimally efficacious 20 mg dose of Compound 1.
It is well known in the art that both efficaciousness and side effects of drugs are commonly concentration-dependent. Increases in tolerability without decreasing efficaciousness, or in some cases while increasing efficaciousness of the drug, can often be accomplished by maintaining blood levels of the drug more consistently between the minimum efficacious concentration and the toxic concentration. See, e.g. Krishnamurthy T N, U.S. Pat. No. 5,215,758 to Euroceltique; Notario G F et al. U.S. Pat. No. 6,872,407 to Abbott Laboratories; Cleary J D et al., Am. J. Health Syst. Pharm. 1999 56 1529; Lyass O et al. Cancer 2000 89: 1037. In certain cases, methods of formulating the drug can help to attain more consistent systemic exposure, but such formulations can be difficult to manufacture, can be expensive due to their proprietary nature, require extensive and costly cross-species in vivo analyses that are not always predictive of human absorption, and can be of limited value if the absorption window for the drug of interest is limited, e.g. to the duodenum, as is often the case (e.g. see Wong P S L et al., U.S. Pat. No. 6,120,803 to Alza and references therein). An alternative approach is to decrease the rate of metabolism of a drug without compromising its beneficial characteristics, if possible, thereby decreasing its rate of clearance. In a drug already given once daily such as Compound 1, increasing its half-life will have the effect of decreasing peak to trough variance when the drug has reached its steady state.
Compound 1 demonstrates relatively few sites of metabolism as demonstrated by rat liver microsome assays. In contrast with a structurally related series of aminoalkylindoles, which are also active cannabinoid receptor ligands, but which are oxidatively metabolized at a number of sites throughout the structure, Compound 1 was found to be subject to hydroxylation only on the pyrazole 3-substituent, i.e. carbon oxidation the N-aminopiperidine ring. See scheme below. Oxidation appears to occur at several sites on the piperidine ring as judged by observation of at least two ring-hydroxylated primary metabolites (designated Ma3 and Ma4 in scheme below) and two dehydro species that presumably resulted either from loss of water from the primary hydroxylated species or potentially by direct dehydrogenation (Ma5 and Ma6 in Scheme I). Further oxidation of these latter metabolites results in the dehydropiperidine alcohols Ma1 and Ma2. Zhang Q et al. Drug Metab. Dispos. 2005 33: 508; Zhang Q et al. Drug Metab. Dispos. 2002 30: 1077; Zhang Q et al. J. Mass Spectrom. 2004 39: 672.

Since compound 1A also possesses a similar chemical structure and the identical aminopiperidine amide functional group, the piperidine of this compound represents a site of potential metabolism as well.
The biological activity of these metabolites has not been publicly reported to the knowledge of the applicant. However, the effect of replacing the piperidine ring of Compound 1 with a variety of other groups has been published, giving an indication of the structure-activity relationship of CB1 antagonist activity with variations at that portion of the molecule. Short-chain alkane substituents attached to the amide nitrogen in place of a piperidine ring are tolerated with minimal loss of CB1 antagonist activity. The corresponding hydroxyalkanes consistently lose substantial CB1 binding affinity. This suggests that Ma1, Ma2, Ma3 and Ma4 will be less active CB1 antagonists than Compound 1; see e.g. Lan R et al., J. Med. Chem. 1999 42: 769; Francisco E Y et al., J Med. Chem. 2002 45: 2708; Katoch-Rouse R et al., J. Med. Chem. 2003 46: 642. These hydroxylated metabolites also present a likely point for Phase II metabolism such as glucuronide or sulfate conjugation and excretion (see for instance Enzyme Systems that Metabolize Drugs and Other Xenobiotics Ionnides C, Ed., 2002, Wiley). Compound 1A shares the pharmacophore of Compound 1 and will have a similar liability for hydroxylated ring metabolites.
Increased polarity and hydrogen bonding capability, particularly hydrogen bond donating ability, are well-correlated with decreased blood-brain barrier penetration (e.g. see Platts J A et al. Eur. J. Med. Chem. 2001 36: 719; Keseru G M and Molnar L, J. Chem. Inf. Comput. Sci. 2001 41: 120; and references therein). Therefore, if the oxidative metabolism of the piperidine ring could be decreased, then for a given dose of Compound 1, a larger amount of active compound would be expected to partition into the brain and reach the central CB1 receptor.
The specific enzymes responsible for the metabolism of Compounds 1 and 1A are, to applicant's knowledge, as yet unreported. However, several important metabolic enzymes responsible for oxidative metabolism, such as cytochrome P450 subtypes 2D6, 2C9, and 2C19, among others, are highly variable between individuals depending on their pharmacogenomic background and can lead to exceedingly large differences in rates of drug metabolism (e.g. Daly A K, Fundam. Clin. Pharmacol. 2003 17: 27; Mancinelli L, AAPS PharmSci 2000 2: E4; Ma MK, Am. J. Health Syst. Pharm. 2002 59: 2061; and references therein). Reducing the susceptibility of a compound to oxidation by these enzymes can decrease the inter-individual pharmacokinetic variability of the drug and enhance its population benefit.
It is therefore desirable to create a compound displaying the beneficial activities of Compounds 1 and 1A, but with a reduced rate of oxidative metabolism.